This invention relates to the common use of estrogen and gestagens for the production of a combination preparation for oral contraception and a corresponding pack containing this combination preparation.
Combination preparations for oral contraception are already known, for example, Femovan(copyright) [DE-PS 2 546 062] or Marvelon(copyright) [DE-OS 2 361 120]. These preparations consist of 21 active ingredient-containing (estrogen/gestagen) dosage units and 7 active ingredient-free coated tablets (sugar pills; placebos). The dose to be administered daily is uniformly high in each case (so-called single-phase preparations) and produces the desired contraceptive effect in the entire intake period and in the intake pause or during the intake of the placebos. In most preparations, a 7-day interruption of the intake of active ingredient-containing dosage units was considered necessary until quite recently to trigger a reliable withdrawal bleeding and thus to achieve a satisfactory cycle control.
Other preparations, which exhibit more than 21 dosage units containing an estrogenic and progestational active ingredient, and in which the intake pause is partially (Ijzerman, Pasquale) or completely (Kuhl) bridged over by estrogen-containing dosage units. In this case, it is possible that the synthetic estrogen ethinylestradiol otherwise contained in oral contraceptives is replaced partially or completely by a conjugated estrogen, preferably estradiol.
A combination preparation for substitution therapy and contraception for females before menopause (approximately starting from the 40th year of life) is known from EP-A-0 253 607. This combination preparation contains an estrogen from the group
17xcex2-Estradiol,
ethinylestradiol and
mestranol
as well as a gestagen from the group
levonorgestrel,
gestodene,
desogestrel,
3-ketodesogestrel and
norethindrone.
A thus selected composition is to offset hormonal irregularities in the transition phase of premenopause and to help alleviate the symptoms caused by the hormonal changeover of the female organism in this phase. Such a composition simultaneously assures a premenopausal female the contraceptive protection still necessary at this age.
The development of new oral contraceptives for females of reproductive age before premenopause was characterized during the last twenty years above all by the reduction of the estrogen and gestagen dosages.
The reduction of the daily hormone dose was connected with the expectation to minimize the frequency of undesired side effects. Epidemiological data collected in the meantime confirm the desired trend toward better compatibility of lower-dosed preparations relative to cardiovascular complications [(1.) Thorogood, M., Oral Contraceptives and Cardiovascular Disease: An Epidemiologic Overview; Pharmaceoepidemiology and Drug Safety, Vol. 2: 3-16 (1993); (2.) Gerstman, B. B.; Piper, J. M.; Tomita, D. K.; Ferguson, W. J.; Stadel., B. V.; Lundin, F. E.; Oral Contraceptive Estrogen Dose and the Risk of Deep Venous Thromboembolic Disease, Am. J. E., Vol. 133, No. 1, 32-36 (1991); (3.) Lidegaard, O., Oral contraception and risk of a cerebral thromboembolic attack: results of a case-control study; BMJ Vol. 306, 956-63 (1993); (4.) Vessey, M.; Mant, D.; Smith, A.; Yeates, D.; Oral contraceptives and venous thromboembolism: findings in a large prospective study; BMJ, Vol. 292, (1986); (5.) Mishell, D. R., Oral Contraception: Past, Present and Future Perspectives; Int. J. Fertil., 36 Suppl., 7-18 (1991)].
It is assumed that a correlation exists above all between the level of the estrogen dose and the incidence of cardiovascular diseases. But the maintenance of the contraceptive effectiveness stands in the way of an extreme reduction of the daily estrogen dose. Although the ovulation-inhibiting effect of the low-dosed oral contraceptives is caused mainly by the gestagenic component, the estrogenic component also makes a significant contribution to the central inhibition action and to the ovarian suppression (ovulation inhibition). Moreover, the daily estrogen dose must not fall below the minimum dose ranges, so that a satisfactory cycle control can be assured (Der Frauenarzt [The Gynecologist]; 34, 7: 793 (1993)].
The lowest estrogen dose contained in an oral contraceptive on the market at this time is 20 xcexcg of ethinylestradiol, combined with 150 xcexcg of desogestrel (Mercilon). Although the cycle control of this preparation is, as expected, somewhat poorer in comparison to preparations with a higher estrogen dose, the high acceptance rate of Mercilon indicates a small clinical relevance of this drawback. But the observation, made identically in several studies, of a lesser ovarial suppression of the preparation containing 20 xcexcg of ethinylestradiol represents a clinically important problem. Obviously with this very low estrogen dose, in the case of many females, the maturation of follicles, which could be detected with ultrasonic studies or hormonal studies, results [(6.) Lunell, N. O.; Carstrxc3x6m, K.; Zador, G.; Ovulation inhibition with a combined oral contraceptive containing 20 xcexcg of ethinylestradiol and 250 xcexcg of levonorgestrel; Acta. Obstet. Gynecol. Scand. Suppl. 88: 17-21 (1979); (7.) Mall-Haefeli, M.; Werner-Zodrow, I.; Huber, P. R.; Klinische Erfahrungen mit Mercilon und Marvelon unter besonderer Berxc3xccksichtigung der Ovar-Funktion [Clinical Experience with Mercilon and Marvelon under special consideration of the ovary function]; Geburtsh. und Frauenheilk. [Obstetrics and Gynecology] 51, 35-38, Georg Thieme Verlag, Stuttgart-New York (1991); (8.) Strobel, E., Behandlung mit oralen Kontrazeptiva [Treatment with Oral Contraceptives]; Fortschr. Med. Vol. 110, No. 20 (1992); (9.) Letter to Editor, Contraception 45: 519-521 (1992); (10.) Teichmann, A. T.; Brill, K.; Can Dose Reduction of Ethinylestradiol in OCs Jeopardize Ovarian Suppression and Cycle Control? Abstract Book, VIIIth World Congress on Human Reproduction, Bali, Indonesia (1993)].
The hormone determinations performed showed that functional granulosa cells that secrete 17xcex2-estradiol are involved. Each intake error in the case of females with clear ovarian activity, thus with follicular maturations, can result in a quick increase of gonadotropin production. The requirements for an ovulation would thus be present. It is estimated that approximately one third of females take oral contraceptives irregularly within one year of use (Gynpress, Volume 1, No. 3, 1990). The risk of a pregnancy is therefore high especially in the case of intake errors with the 20 xcexcg ethinylestradiol preparations.
The object of this invention is an improved single-phase combination preparation for a female of reproductive age, who is not yet in premenopause, containing an estrogen and gestagen in each individual dosage unit, with the lowest possible estrogen content in each individual dosage unit, but also with a low total hormone content per administration cycle.
It has now been found that a pronounced ovarian suppression without frequent follicular maturations with low daily estrogen dosage, low total estrogen as well as low total hormone amount per administration cycle can be achieved by the use of a composition comprising an estrogen selected from
2.0 to 6.0 mg of 17xcex2-estradiol and
0.015 to 0.020 mg of ethinylestradiol,
and a gestagen selected from
0.05 to 0.075 mg of gestodene,
0.075 to 0.125 mg of levonorgestrel,
0.06 to 0.15 mg of desogestrel,
0.06 to 0.15 mg of 3-ketodesogestrel,
0.1 to 0.3  1 to 3 mg of drospirenone,
0.1 to 0.2  1 to 2 mg of cyproterone acetate,
0.2 to 0.3 mg of norgestimate and
 greater than 0.35 to 0.75 mg of norethisterone.
for the production of a form of dosage for contraception for a female of reproductive age, who has not yet reached premenopause, by administration of the form of dosage for 23 or 24 days, beginning on day one of the menstrual cycle (first day of menstrual bleeding), followed by 5 or 4 pill-free or sugar pill days, during a total of 28 days in the administration cycle.
The terms xe2x80x9cpremenopausexe2x80x9d and xe2x80x9cmenopausexe2x80x9d are used within the scope of this invention in the meaning of the conventional definition, see, for example, xe2x80x9cThe Controversial Climacteric,xe2x80x9d P. A. of Keep et al., Ed., MTP press (1981), e.g., p. 9.
The daily hormone dose is kept to a very low level here, while the usual 21-day intake is extended by two or three days. The remaining 5 or 4 days of a cycle are preferably bridged over by placebos, to avoid intake errors, or by 5 or 4 intake-free days.
According to a preferred embodiment of this invention, this relates to the use of a composition comprising an estrogen selected from
 greater than 2.0 to 6.0 mg of 17xcex2-estradiol and
0.020 mg of ethinylestradiol;
and a gestagen selected from
 greater than 0.06 to 0.075 mg of gestodene,
 greater than 0.100 to 0.125 mg of levonorgestrel,
 greater than 0.10 to 0.15 mg of desogestrel,
 greater than 0.10 to 0.15 mg of 3-ketodesogestrel,
0.25 to 0.30  2.5 to 3.0 mg of drospirenone,
0.1 to 0.2  1 to 2 mg of cyproterone acetate,
0.2 to 0.3 mg of norgestimate and
0.50 to 0.75 mg of norethisterone
for the production of a form of dosage for contraception as described above.
In addition, this invention relates to a combination product for oral contraception, which comprises
a) 23 or 24 dosage units, each containing an estrogen selected from
 greater than 2.0 to 6.0 mg of 17xcex2-estradiol and
0.020 mg of ethinylestradiol;
and a gestagen selected from
 greater than 0.06 to 0.075 mg of gestodene,
 greater than 0.100 to 0.125 mg of levonorgestrel,
 greater than 0.10 to 0.15 mg of desogestrel,
 greater than 0.10 to 0.15 mg of 3-ketodesogestrel,
0.25 to 0.30  2.5 to 3.0 mg of drospirenone,
0.1 to 0.2  1 to 2 mg of cyproterone acetate,
0.2 to 0.3 mg of norgestimate and
0.50 to 0.75 mg of norethisterone
and
b) 5 or 4 sugar pills or other indications to show that the daily administration of 23 or 24 dosage units is to be followed by 5 or 4 pill-free or sugar pill days are to be followed.